1. Field of the Invention
This invention relates to a novel process for preparing azidomethylthienylacetic acids and certain esters thereof useful in the synthesis of aminomethylthienylmethylpenicillins and aminomethylthienylmethylcephalosporins. The novel azidomethylthienylacetic acids are prepared by oxidative rearrangement of azidomethylthienylmethyl ketones by thallium (III) nitrate in the presence of methanol or ethanol and certain specified acids to provide the methyl azidomethylthienylacetates when methanol is employed or the corresponding ethyl esters when ethanol is used. The azidomethylthienylacetic acids are obtained by hydrolysis of the esters. The azidomethyl compounds provided by the process of the invention are useful intermediates in the preparation of aminomethylthienylmethylpenicillins and -cephalosporins by acylation of 6-APA, 7-ACA or their derivatives to obtain corresponding azidomethylthienylmethyl compounds which are then converted to the analogous aminomethyl compounds by well-known means. British Pat. No. 1,467,407 (Derwent No. 73775V) discloses a similar process employing amino-protected methyl 5-aminomethyl-2-thienyl ketones to provide the corresponding 2-thienylacetic acids. However, the use of methyl azidomethylthienyl ketones is novel and unexpected in view of the prior art which discloses that alkyl azides are unstable to acids such as those employed in the present process.
2. Description of the Prior Art
McKillop et al., J. Am. Chem. Soc., 93, 4919 (1971) has shown that thallium (III) nitrate in methanol containing perchloric acid converts acetophenones into methyl phenylacetates. However, in defining the limitations of this conversion the author points out that the reaction is unsuccessful when applied to compounds containing an amino group due to preferential complexation of the amino substituent with the thallium electrophile. The corresponding amides are stated to react normally. The above-mentioned British Pat. No. 1,467,407 discloses that amino protected 5-aminomethyl-2-thienylacetic acids may be prepared by reaction of amino protected 2-acetyl-5-aminomethylthiophenes with thallium (III) nitrate in the presence of lower alkanols such as methanol and perchloric acid followed by hydrolysis of the intermediate ester. The use of the amino protected 5-aminomethyl-2-thienylacetatic acids or a reactive functional derivative thereof to acylate certain 7-aminocephalosporanic acids and derivatives thereof followed by removal of the amino protecting group to provide the corresponding 7-(5-aminomethyl-2-thienylmethyl)cephalosporins is also described.
U.S. Pat. Nos. 3,966,710 and 3,997,527 disclose a series of aminomethylarylmethylpenicillins, particularly 6-(phenyl- and thienylacetamido)penicillanic acids and esters substituted in the phenyl and thienyl moieties with an aminomethyl substituent. The aminomethylarylacetic acid intermediates employed, including 2-aminomethyl-3-thienylacetic acid and 3-aminomethyl-2-thienylacetic acid were prepared by conventional synthetic methods. The former compound was prepared from 2-aminomethyl-3-methylthiophene by acetylation, free radical catalyzed bromination to obtain N-acetyl-2-aminomethyl-3-bromomethylthiophene; this intermediate was then converted to the 3-cyanomethyl analog which was hydrolyzed to the desired 3-thienylacetic acid. The isomeric 3-aminomethyl-2-thienylacetic acid was obtained from 2-thienylacetamide via the corresponding N-hydroxymethyl compound, cyclization to 3-aminomethyl-2-thienylacetic acid lactam and hydrolysis.
The amino moiety of the aminomethyl substituted arylacetic acids was protected, preferably by reaction with methyl acetoacetate as taught in U.S. Pat. No. 3,813,376, prior to acylation of 6-APA or its esters.
o-Azidomethylphenylacetic acid and methods for its preparation from o-bromomethylphenylacetate esters are disclosed in U.S. Pat. Nos. 3,766,175; 3,813,391; 3,814,755 and 3,840,535. However, the azidomethylthienylacetic acids and esters are not known in the art.
Abramovitch and Kyba in "The Chemistry of the Azido Group", S. Patai, Editor, Interscience Publishing Co., New York, 1971, Chapter 5, pp. 221-239, record that alkyl azides, including aralkyl azides, are unstable in the presence of protonic acids such as sulfuric, hydrochloric, perchloric and trifluoroacetic acids, especially upon warming. Such azides are also reported to be unstable to Lewis acids such as aluminum trichloride and antimony pentachloride.